Doxorubicin (DOX), also known as adriamycin, is an anthracycline antibiotic that has been used extensively over the past four decades to treat a wide variety of solid and hematopoietic tumors. The anthracyclines are a family of chemically-related anthraquinone-glycoside compounds of natural and synthetic origin. Many of the anthracyclines, including DOX and daunorubicin (DNR), another widely used anthracycline anti-cancer drug, target the cell nucleus and function principally as topoisomerase II poisons, locking the DNA/topoisomerase II cleavable complex through DNA intercalation of the anthracyclines' relatively planar anthraquinone structure. The poisoning of topoisomerase II promotes the accumulation of double-stranded DNA breaks, which, in turn, triggers apoptosis. See Froelich-Ammon, S. J. and Osheroff, N., J. Biol. Chem. 270, 21429-21432 (1995).
As a clinical agent, the efficacy of DOX is often limited by multiple mechanisms of cellular drug resistance, including the overexpression of transmembrane multidrug transporters, tumor suppressor protein dysfunction, and the expression of anti-apoptotic Bcl-2 protein family members. See Booser, D. J. and Hortobagyi, G. N., Drugs, 47, 223-258 (1994); Hill, M. E., et al., Blood, 88, 1046-1051 (1996); and Lowe, S. W., et al., Science, 266, 807-810 (1994). In addition, systemic toxicities often affecting rapidly dividing hematopoietic and epithelial cells limit the doses of drugs that are administered.
The therapeutic efficacy of DOX at cumulative doses in excess of 450 mg/m2 is further limited by its association with well-defined, life-threatening cardiotoxicities. See Acton, E. M. in “Anthracycline Antibiotics. Novel Analogs, Methods of Delivery and Mechanisms of Action,” Priebe, W., ed., Washington, D.C.: American Chemical Society, 1995, 1-13; and Frishman, W. H. et al., Curr. Probl. In Cardiol., 21, 225-288 (1996). This cardiotoxicity is possibly the result of the generation of reactive oxygen species (ROS) by the anthracycline's anthraquinone backbone. The ROS can disrupt sarcoplasmic reticulum function, induce cardiomyocyte apoptosis, and impede myocardial contractility. The most pronounced cardiotoxic effect is cardiomyopathy (weakness of the heart) due to chronic myocardial insult. Severe DOX-induced cardiomyopathies most often present clinically as congestive heart failure with a dose-dependent probability attaining 20% at cumulative doses as low as 600 mg/m2, with subsequent 50% mortality after two years without transplantation. See Frishman, W. H., et al., Curr. Probl. In Cardiol., 21, 225-288 (1996); and Jensen, B. V., et al., Ann. Oncol., 13, 699-709 (2002). In addition to this chronic effect, DOX and other commonly used anthracyclines induce acute, but often reversible, eletrocardiographic changes. See Frishman, W. H. et al., Curr. Probl. In Cardiol., 21, 225-288 (1996).
Frequency and severity of cardiotoxicity also have been observed to increase with the use of combination drug therapies involving anthracyclines. Most notably, a dramatically higher frequency of heart failure has been observed in clinical trials for a breast cancer treatment that pairs DOX with the humanized anti-erbB-2 antibody trastuzumab (HERCEPTIN®; Genentech, Inc., South San Francisco, Calif., United States of America) and cyclophosphamide (26%), or with trastuzumab in combination with paclitaxel (13%). See Salmon. D. J., et al., N. Engl. J. Med., 344, 783-792 (2001). Additionally, cardiovascular damage is seen in the use of the chemotherapeutic regimen CHOP (the combination of cyclophosphamide, DOX, vinblastine, and prednisone) for Non-Hodgkins lymphoma. See Limat, S., et al., Ann. Oncol., 14, 277-281 (2003).
Thus, there exists a need in the art for improved anthracycline anti-cancer agents that circumvent cellular drug resistance mechanisms and have reduced cardiotoxicity. In particular, there is a need for anthracycline anti-cancer agents having reduced cardiotoxicity, but which also maintain good cytoxicity toward cancer cells.